Substituted amino acids as integrin inhibitors

Abstract

The invention relates to compounds of formula (I):or a salt thereof, wherein R1, G, L1, L2, L3, and Y are as described herein. Compounds of formula (I) and pharmaceutical compositions thereof are inhibitors of one, or both of, αvβ1 integrin and αvβ6 integrin that are useful for treating fibrosis such as in nonalcoholic steatohepatitis (NASH), idiopathic pulmonary fibrosis (IPF) and nonspecific interstitial pneumonia (NSIP).

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl optionally substituted by R 4 , 1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl optionally substituted by R 4 , 6-aminopyridin-2-yl optionally substituted by R 4 , or (pyridin-2-yl)amino optionally substituted by R 4 ; 
 G is —C(O)R 2  or R 3 ; 
 R 2  is C 1 -C 6  alkyl optionally substituted by R 2a , C 3 -C 8  cycloalkyl optionally substituted by R 2b , 3- to 12-membered heterocyclyl optionally substituted by R 2c , C 6 -C 14  aryl optionally substituted by R 2d , 5- to 10-membered heteroaryl optionally substituted by R 2e , —OR 2f , or —NR 2g R 2h ; 
 R 3  is C 1 -C 6  alkyl optionally substituted by R 3a , C 3 -C 8  cycloalkyl optionally substituted by R 3b , 3- to 12-membered heterocyclyl optionally substituted by R 3c , C 6 -C 14  aryl optionally substituted by R 3d , or 5- to 10-membered heteroaryl optionally substituted by R 3e ; 
 L 1  is C 2 -C 4  alkylene optionally substituted by R 4 ; 
 L 2  is a bond or C 1 -C 3  alkylene optionally substituted by R 4 ; 
 L 3  is C 2 -C 4  alkylene optionally substituted by R 4 ; 
 Y is a bond or C 3 -C 8  cycloalkylene optionally substituted by Y a ; 
 R 2f  is C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, 3- to 12-membered heterocyclyl, C 6 -C 14  aryl, or 5- to 10-membered heteroaryl, wherein the C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, 3- to 12-membered heterocyclyl, C 6 -C 14  aryl, and 5- to 10-membered heteroaryl of R 2f  are independently optionally substituted by R 2i , 
 R 2g  and R 2h  are each independently hydrogen, deuterium, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, 3- to 12-membered heterocyclyl, C 6 -C 14  aryl, or 5- to 10-membered heteroaryl, wherein the C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, 3- to 12-membered heterocyclyl, C 6 -C 14  aryl, and 5- to 10-membered heteroaryl of R 2g  and R 2h  are independently optionally substituted by R 2j ; 
 each R 2a , R 2b , R 2c , R 2d , R 2e , R 2i , R 2j , R 3a , R 3b , R 3c , R 3d , R 3e  and Y a  is independently oxo or R 4 ; 
 each R 4  is independently deuterium, halogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, 3- to 12-membered heterocyclyl, C 6 -C 14  aryl, 5- to 10-membered heteroaryl, —CN, —OR 5 , —SR 5 , —NR 6 R 7 , —NO 2 , —C═NH(OR 5 ), —C(O)R 5 , —OC(O)R 5 , —C(O)OR 5 , —C(O)NR 6 R 7 , —NR 5 C(O)R 6 , —NR 5 C(O)OR 6 , —NR 5 C(O)NR 6 R 7 , —S(O)R 5 , —S(O) 2 R 5 , —NR 5 S(O)R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 6 R 7 , —S(O) 2 NR 6 R 7 , or —P(O)(OR 5 )(OR 6 ), wherein the C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, 3- to 12-membered heterocyclyl, C 6 -C 14  aryl, and 5- to 10-membered heteroaryl of R 4  are independently optionally substituted by R 4a ; 
 each R 4a  is independently deuterium, halogen, oxo, —OR 8 , —NR 8 R 9 , —C(O)R 8 , —C(O)OR 8 , —NR 8 C(O)OR 10 , —CN, —S(O)R 8 , —S(O) 2 R 8 , —P(O)(OR 8 )(OR 9 ), C 3 -C 8  cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C 6 -C 14  aryl, or C 1 -C 6  alkyl, wherein the 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C 6 -C 14  aryl, and C 1 -C 6  alkyl of R 4a  are independently optionally substituted by R 4b , 
 each R 4b  is independently deuterium, oxo, —OH, —O( 2 H), halogen, or C 1 -C 6  alkyl optionally substituted by deuterium, halogen, —OH, —O( 2 H), or oxo; 
 each R 5  is independently hydrogen, deuterium, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 6 -C 14  aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 6 -C 14  aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl of R 5  are each independently optionally substituted by R 5a ; 
 each R 5a  is independently halogen, deuterium, oxo, —CN, —OR 10 , —NR 11 R 12 , —P(O)(OR 11 )(OR 12 ), 3- to 12-membered heterocyclyl, or C 1 -C 6  alkyl optionally substituted by deuterium, halogen, —OH, —O( 2 H), or oxo; 
 each R 6  is independently hydrogen, deuterium, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 6 -C 14  aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocyclyl, wherein the C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 6 -C 14  aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl of R 6  are independently optionally substituted by deuterium, halogen, oxo, —CN, —OR 10 , —NR 11 R 12 , or C 1 -C 6  alkyl optionally substituted by deuterium, halogen, —OH, —O( 2 H), or oxo; 
 each R 7  is independently hydrogen, deuterium, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 6 -C 14  aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocyclyl, wherein the C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 6 -C 14  aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl of R 7  are independently optionally substituted by deuterium, halogen, oxo, —CN, —OR 10 , —NR 11 R 12 , or C 1 -C 6  alkyl optionally substituted by deuterium, halogen, —OH, —O( 2 H), or oxo;
 or R 6  and R 7  are taken together with the atom to which they are attached to form a 3- to 10-membered heterocyclyl optionally substituted by deuterium, halogen, oxo, —OR 10 , —NR 11 R 12 , or C 1 -C 6  alkyl optionally substituted by deuterium, halogen, oxo, —OH, or —O( 2 H); 
 
 each R 8  is independently hydrogen, deuterium, C 1 -C 6  alkyl optionally substituted by deuterium, halogen, or oxo, C 2 -C 6  alkenyl optionally substituted by deuterium, halogen, or oxo, or C 2 -C 6  alkynyl optionally substituted by deuterium, halogen, or oxo; 
 each R 9  is independently hydrogen, deuterium, C 1 -C 6  alkyl optionally substituted by deuterium, halogen, or oxo, C 2 -C 6  alkenyl optionally substituted by deuterium, halogen, or oxo, or C 2 -C 6  alkynyl optionally substituted by deuterium, halogen, or oxo; 
 each R 10  is independently hydrogen, deuterium, C 1 -C 6  alkyl optionally substituted by deuterium, halogen, or oxo, C 2 -C 6  alkenyl optionally substituted by deuterium, halogen, or oxo, or C 2 -C 6  alkynyl optionally substituted by deuterium, halogen, or oxo; 
 each R 11  is independently hydrogen, deuterium, C 1 -C 6  alkyl optionally substituted by deuterium, halogen, or oxo, C 2 -C 6  alkenyl optionally substituted by deuterium, halogen, or oxo, or C 2 -C 6  alkynyl optionally substituted by deuterium, halogen, or oxo; and 
 each R 12  is independently hydrogen, deuterium, C 1 -C 6  alkyl optionally substituted by deuterium, halogen, or oxo, C 2 -C 6  alkenyl optionally substituted by deuterium, halogen, or oxo, or C 2 -C 6  alkynyl optionally substituted by deuterium, halogen, or oxo; 
 or R 11  and R 12  are taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by deuterium, halogen, oxo or C 1 -C 6  alkyl optionally substituted by deuterium, oxo, or halogen. 
 
       
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 1  is C 2  alkylene optionally substituted by R 10  or L 1  is —CH 2 CH 2 —. 
     
     
         3 .- 4 . (canceled) 
     
     
         5 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
 -L 1 -O-L 2 -Y-L 3 - are taken together to form a moiety selected from the group consisting of:   
       
         
           
           
               
               
           
         
         is a C 3 -C 8  cycloalkylene optionally substituted by Y a , and 
       
       
         
           
           
               
               
           
         
         is a C 3 -C 8  cycloalkylene optionally substituted by Y a . 
       
     
     
         6 .- 8 . (canceled) 
     
     
         9 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
 G is —C(O)R 2 , and   R 2  is:
 (i) C 1 -C 6  alkyl substituted by 0-5 R 2a  groups, 
 each of the R 2a  groups is independently selected from the group consisting of: halogen, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, 3- to 12-membered heterocyclyl, C 6 -C 14  aryl, 5- to 10-membered heteroaryl, —CN, —OR 5 , —NR 6 R 7 , —NR 5 C(O)OR 6 , and —S(O) 2 R 5 , 
 each of the C 1 -C 6  alkyl, the C 3 -C 8  cycloalkyl, the 3- to 12-membered heterocyclyl, the C 6 -C 14  aryl, and the 5- to 10-membered heteroaryl is independently substituted by 0-5 R 4a  groups, and 
 each R 5  of the —OR 5  is independently selected from the group consisting of: hydrogen, C 1 -C 6  alkyl, and substituted or unsubstituted C 6 -C 14  aryl, 
 (ii) C 3 -C 8  cycloalkyl substituted by 0-5 R 2b  groups, and 
 each of the R 2b  groups is independently selected from the group consisting of: halogen, C 1 -C 6  alkyl substituted by 0-5 R 4a  groups, C 6 -C 14  aryl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, and —OR 5 , 
 (iii) 3- to 12-membered heterocyclyl substituted by 0-5 R 2c  groups, 
 each of the R 2c  groups is independently selected from the group consisting of: oxo, halogen, C 1 -C 6  alkyl substituted by 0-5 R 4a  groups, C 6 -C 14  aryl, 5- to 10-membered heteroaryl substituted by 0-5 halogen or 0-5 C 1 -C 6  alkyl, —CN, —OR 5 , —C(O)R 5 , —C(O)OR 5 , —S(O) 2 R 5 , and —NR 5 C(O)OR 10 , and 
 each R 5  of the —OR 5 , the —C(O)R 5 , the —C(O)OR 5 , or the —S(O) 2 R 5  is independently C 1 -C 6  alkyl, 
 (iv) C 6 -C 14  aryl substituted by 0-5 R 2d  groups, 
 each of the R 2d  groups is independently selected from the group consisting of: halogen, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, —CN, and —OR 5 , and 
 each of the C 1 -C 6  alkyl, the C 3 -C 8  cycloalkyl, the 3- to 12-membered heterocyclyl, and the 5- to 10-membered heteroaryl is independently substituted by 0-5 halogen, C 1 -C 6  alkyl, or —OR 8 , 
 (v) 5- to 10-membered heteroaryl substituted by 0-5 R 2e  groups, 
 each of the R 2e  groups is independently selected from the group consisting of: 
   halogen, —CN, C 1 -C 6  alkyl substituted by 0-5 halogen groups, and —OR 5 ;
 (vi) —OR 2f , 
 R 2f  is selected from the group consisting of: C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, 3- to 12-membered heterocyclyl, C 6 -C 14  aryl, and 5- to 10-membered heteroaryl, each of which is substituted by 0-5 R 2i  groups, 
 each of the R 2i  groups is selected from the group consisting of: halogen, C 1 -C 6  alkyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, 3- to 12-membered heterocyclyl, C 6 -C 14  aryl, 5- to 10-membered heteroaryl, —C(O)R 5 , —C(O)OR 5 , —S(O) 2 R 5 , —OR 5 , —NR 5 C(O)R 6 , and —NR 5 C(O)OR 6 , and 
 each of the C 1 -C 6  alkyl, the C 2 -C 6  alkynyl, the C 3 -C 8  cycloalkyl, the 3- to 12-membered heterocyclyl, the C 6 -C 14  aryl, the C 6 -C 14  aryl, and the 5- to 10-membered heteroaryl is independently substituted by 0-5 halogen, —CN, —OR 8 , C 1 -C 6  alkyl, or C 6 -C 14  aryl, or 
 (vii) —NR 2g R 2h , and 
 R 2g  is hydrogen and R 2h  is C 1 -C 6  alkyl substituted by 0-5 halogen, or R 2g  is C 1 -C 6  alkyl substituted by 0-5 halogen and R 2h  is C 1 -C 6  alkyl substituted by 0-5 halogen. 
   
     
     
         10 - 106 . (canceled) 
     
     
         107 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
 G is —C(O)R 2 , and   R 2  is selected from the group consisting of:   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         108 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
 G is —C(O)R 2 , and   R 2  is selected from the group consisting of:   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         109 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
 G is —C(O)R 2 , and   R 2  is selected from the group consisting of:   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         110 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
 G is R 3 , and   R 3  is 5- to 10-membered heteroaryl substituted by 0-5 R 3e  groups, and   each of the R 3e  groups is independently selected from the group consisting of: halogen, C 1 -C 6  alkyl optionally substituted by halogen, C 6 -C 14  aryl, 5- to 10-membered heteroaryl optionally substituted by halogen or C 1 -C 6  alkyl, and C 1 -C 6  alkoxy.   
     
     
         111 .- 118 . (canceled) 
     
     
         119 . The compound of  claim 110 , or a pharmaceutically acceptable salt thereof, wherein:
 G is R 3 , and   R 3  is selected from the group consisting of:   
       
         
           
           
               
               
           
         
       
       and
 each R 3e  is independently R 4 . 
 
     
     
         120 . The compound of  claim 110 , or a pharmaceutically acceptable salt thereof, wherein:
 G is R 3 , and   R 3  is selected from the group consisting of:   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         121 . The compound of  claim 110 , or a pharmaceutically acceptable salt thereof, wherein:
 G is R 3 , and   R 3  is selected from the group consisting of:   
       
         
           
           
               
               
           
         
       
     
     
         122 .- 140 . (canceled) 
     
     
         141 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 
     
     
         142 . A method of treating a fibrotic disease in an individual in need thereof, the method comprising:
 administering a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the fibrotic disease is selected from the group consisting of: pulmonary fibrosis, liver fibrosis, skin fibrosis, cardiac fibrosis, kidney fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, and biliary fibrosis.   
     
     
         143 . (canceled) 
     
     
         144 . A kit comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and instructions for the treatment of a fibrotic disease. 
     
     
         145 . (canceled) 
     
     
         146 . A method of inhibiting αvβ 6  integrin in an individual, the method comprising:
 administering a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
 
     
     
         147 . A method of inhibiting TGFβ activation in a cell, the method comprising:
 administering to the cell a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
 
     
     
         148 . (canceled) 
     
     
         149 . A method of modulating at least one integrin in a subject, the at least one integrin comprising an αv subunit, the method comprising:
 administering to the subject an effective amount of the compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein: 
 the subject has or is at risk of a fibrotic disease selected from the group consisting of: idiopathic pulmonary fibrosis (IPF), interstitial lung disease, radiation-induced pulmonary fibrosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic liver disease induced fibrosis, Alport syndrome, primary sclerosing cholangitis (PSC), primary biliary cholangitis, biliary atresia, systemic sclerosis associated interstitial lung disease, scleroderma, diabetic nephropathy, diabetic kidney disease, focal segmental glomerulosclerosis, chronic kidney disease, and Crohn's Disease, 
 the at least one integrin comprises at least one of αvβ 1  integrin and αvβ 6  integrin, and 
 the modulating comprises inhibiting the at least one integrin in the subject, thereby treating the fibrotic disease in the subject. 
 
     
     
         150 .- 155 . (canceled) 
     
     
         156 . A method of modulating TGFβ activation in a cell, the method comprising:
 contacting the cell with the compound of  claim 1 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of  claim 141 , wherein: 
 the modulating comprises inhibiting TGFβ activation in the cell, and 
 the TGFβ activation is mediated in the cell by at least one of αvβ 1  integrin and αvβ 6  integrin. 
 
     
     
         157 .- 158 . (canceled) 
     
     
         159 . A method of treating a subject in need thereof, the method comprising:
 administering to the subject a therapeutically effective amount of the compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein:   the subject has at least one tissue in need of therapy,   each tissue of the at least one tissue has at least one elevated level of:
 TGFβ activation and/or expression; 
 αvβ 1  integrin activity and/or expression; or 
 αvβ 6  integrin activity and/or expression; and 
   the at least one elevated level of the at least one tissue is elevated compared to a healthy state of the at least one tissue,   each tissue of the at least one tissue is selected from the group consisting of: lung tissue, liver tissue, skin tissue, cardiac tissue, kidney tissue, gastrointestinal tissue, gall bladder tissue, and bile duct tissue, and   (i) the method selectively inhibits αvβ 1  integrin compared to αvβ 6  integrin in the subject,   (ii) the method selectively inhibits αvβ 6  integrin compared to αvβ 1  integrin in the subject,   (iii) the method inhibits both of αvβ 1  integrin and αvβ 6  integrin in the subject, or   (iv) the method selectively inhibits both αvβ 1  integrin and αvβ 6  integrin compared to at least one other αv-containing integrin in the subject.   
     
     
         160 .- 166 . (canceled)